This research project was designed to gain insight into the mechanism(s) of protein-uria in NZB/W hybrid mice, an animal model of spontaneous immune complex golmerulonephritis. Increase in glomerular permeability will be assessed by means of probe molecules of known molecular size (horseradish peroxidase, catalase and ferritin) injected systemically and detected in tissues and by urinary protein quantitation and electrophoresis. The specific objectives are: 1) to define the route and extent of protein leakage during the induction and progression of glomerulonephritis; 2) to determine whether slit diaphragm substructure alterations and decrease in sialic acid content of pedicels occur prior to and/or during glomerular permeability increase and 3) to correlate glomerular permeability characteristics with such features as: altered glomerular structure and histochemical (sialic acid) composition, immunopathologic, serologic and clinical findings. The rationale is based upon a body of experimental evidence indicating that during the proteinuric state the glomerulus is more permeable to a variety of substances. It is anticipated that changes in slit pore complex, mediated by a variety of agents, including immunologic mechanisms, might be, at least in part, responsible for protein leakage. In addition, it is expected that the glomerular basement membrane be more permeable to such tracers, probably at the vicinity or in areas where immune complexes are deposited. Proteinuria is a common manifestation of glomerular disease and the principal component of the nephrotic syndrome. A better understanding of the mechanism(s) of proteinuria in these animals is thus relevant because of the similarities between the nephritis of NZB/W mice and immune complex nephritis in man, particularly lupus nephritis. If the route of protein loss, as well as structural components involved in such leakage, can be defined the conclusions drawn in these studies will be verified, later, in animals subjected to experimental procedures which might facilitate or oppose increase in glomerular permeability.